PROJECT SUMMARY/ABSTRACT Our goal is to understand platelet (Plt) production and function upon aging. Plts play essential roles in hemostasis, the process of preventing bleeding, and also participate in immune regulation. Aging is associated with a dramatic increase in platelet-related disorders, including alterations in Plt numbers (thrombocytosis or thrombocytopenia) and in Plt activity. Plts have a very short half-life and are continually produced by hematopoietic stem cells (HSCs). We have discovered that the differentiation pathways of Plt production are different in young and old mice. Here, we propose to investigate the molecular and cellular mechanisms behind the aging-specific differentiation path, and the consequences for Plt function and aging physiology. We hypothesize that the aging-specific Plt pathway contributes to the dramatically increased risk for Plt-related disorders in the elderly. Our discovery of a new, age-specific differentiation pathway provides a unique opportunity for novel discoveries towards mitigating Plt-related disorders, including thrombosis and cardiovascular disease, in the elderly.